标题：Structure Requirements for 4-Aryl-4H-Chromenes as Apoptosis Inducers Using 3D QSAR Methods and Docking Studies
作者：Liu, Zhen; Li, Yan; Ren, Hong; Zhang, Shuwei; Wang, Yonghua; Li, Guohui; Yang, Ling
作者机构：[Liu, Zhen; Li, Yan; Zhang, Shuwei] Dalian Univ Technol, Sch Chem Engn, Dalian 116012, Liaoning, Peoples R China.; [Ren, Hong] Shandong Univ, Sch Me 更多
通讯作者地址：[Li, Y]Dalian Univ Technol, Sch Chem Engn, Dalian 116012, Liaoning, Peoples R China.
来源：ASIAN JOURNAL OF CHEMISTRY
关键词：Chromenes; Apoptosis inducer; CoMFA; CoMSIA; Caspase-3; Tubulin
摘要：Presently, a computational study based on the combinational use of 3D-quantitative structure-activity relationship analyses (QSAR) methods including both the comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) approaches and molecule docking was conducted on a series of 124 types of 4-aryl-4H-chromenes of 24 diverse structural scaffolds as promising novel apoptosis inducers, with purpose to explore the requisite structural features influencing their activity of caspase-3 activation in human breast tumor cells. The obtained 3D-QSAR models exhibited proper reliability and predictivity, where the optimal comparative molecular field analysis and comparative molecular similarity analysis ones gave leave-one-out cross-validation coefficient Q(2) of 0.508 and 0.477, conventional cross-validation coefficient R-ncv(2), of 0.888 and 0.816 for the training set and predictive correlation coefficients R-prc(2) of 0.604 and 0.150 for the independent test set, respectively. Analyses of the derived contour maps reveal that steric substituents at positions 4, 9-13, 15 and 16 favour the apoptosis inducing activity and electron-withdrawing groups at 6 and 10 positions or electron-donating groups at position-7 enhance the activity. Further docking study validates that 4-aryl-4H-chromenes bind at the colchicine site of tubulin and several hydrogen bonds serve to stabilize the ligand-tubulin complex. These models and the derived information, would be of value for further exploration of the apoptosis inducing mechanism and the screening of novel potent chromene-based apoptosis inducers.